The present invention relates generally to a family of biological mediators of immune function associated with nonphysiological conditions. More specifically, it is concerned with purified and isolated leukocyte chemotactic factors released from injured tissue.
Biological mediators such as leukocyte chemotactic factors stimulate the migration of neutrophils from circulation into sites of infection or tissue damage. These mediators are also believed to increase cell adhesion to injured sites and to activate neutrophils to release toxic agents such as oxygen metabolites and proteases. Due to these beneficial characteristics, the nature and source of these mediators have been extensively studied. It has been believed they are primarily derived from low molecular weight serum protein components, that is, from complement-split products C3a and C5a and fibrin-split peptide products as well as from activated immune cells such as leukotriene B.sub.4, LTB.sub.4, and interleukin-8, IL-8. Type I collagen and the synthetic tripeptide f-Met-Leu-Phe are also chemotactically active for both neutrophils and mononuclear cells.
The mechanism for neutrophil recruitment associated with tissue injury is not clear. Serum-derived leukocyte chemotactic factors, such as activated complement components C3a and C5a, have been suggested as playing a role in such a process. Specifically, the interrelationship between ischemic myocardial tissue and inflammatory cells has led to the suggestion that the chemical recruitment signal attracting the neutrophils into infarcted myocardium may be the result of one or more of the following four mechanisms:
1) Serum-derived C3a that is generated from the interactions of tissue protease found in myocardium and the third complement component, PA1 2) Serum-derived C5a generated from the interactions of lysosomal granules of neutrophils that have responded to the initial chemotactic stimulus in the infarcted myocardium and the fifth complement component, PA1 3) A superoxide-dependent factor generated from the interaction of superoxide radicals released by activated neutrophils and latent chemotactic factors present in extracellular fluids, or PA1 4) Platelet-activated factors and arachidonic acid metabolites released by accumulated neutrophils.
To date, the initial signals that recruit and activate the neutrophils during ischemia have not been defined and it is not known whether injured tissue directly participates in the influx of circulating leukocytes by releasing mediators which recruit neutrophils to the sites of the injury.